Whiplash and its associated syndromes continue to be ranked among the most common and debilitating nonfatal injuries. Painful injury of the cervical facet capsule occurs because altered neck motions during whiplash results in mechanical injury to the sensory afferents in the facet joint's capsule. However, due to a lack of relevant in vivo systems modeling biomechanical neck injuries, little is known about the mechanisms of neck pain resulting from whiplash. We recently developed a rat model that simulates the biomechanical loading conditions of the cervical facet joint during whiplash. It is the long-term objective of this application to use that model to define the effects of local joint biomechanics on capsule afferent responses, spinal mechanisms of nociception, and the resulting behavioral sensitivity. We hypothesize that: (1) whiplash-like loading of the facet joint produces persistent pain via altered neurochemical function of the peptidergic and non-peptidergic C- fibers in the facet capsule, (2) the biochemical responses of those capsule afferents have permanent effects on neuropeptides, neurotrophins and immune responses (i.e. glial activation, pro-inflammatory cytokines) in the spinal cord, and (3) whiplash loading produces inflammation in the facet joint that also exacerbates spinal modifications and pain symptoms. We have pilot data demonstrating that a transient whiplash-like loading scenario produces both persistent behavioral sensitivity in the neck and sustained spinal modifications in our rat model. In this proposal we will define the temporal relationship between joint biomechanics, neuropeptide and neurotrophin regulation and immune responses in the dorsal root ganglion and spinal cord, and behavioral sensitivity. In Aim 1 we will define these responses for painful whiplash loading to the C6/C7 facet joint. In Aim 2 we use saporin conjugates in separate studies to selectively eliminate NK1 receptor-bearing and IB4-positive neurons in the facet joint and define their relative contributions to pain and nociception by comparison to outcomes in Aim 1. In Aim 3 we will impose a non-painful joint loading scenario and also ablate NK1 receptor- bearing neurons in the spinal cord to identify which spinal responses are specific for painful joint biomechanics. Lastly, in Aim 4 we will test if inhibiting the inflammatory cascade in the facet joint can prevent or attenuate sensitivity and/or modulate associated spinal responses. By accomplishing the specific aims of this research, we will directly link the initial mechanical conditions of the facet joint to pain pathways in the central nervous system. In turn, we will define the etiology for persistent pain from neck loading, leading to the development of potential treatments to treat whiplash-related neck pain.